2. Academic Validation
  3. Pharmacokinetic profiling of ZCL-278, a cdc42 inhibitor, and its effectiveness against chronic kidney disease

Pharmacokinetic profiling of ZCL-278, a cdc42 inhibitor, and its effectiveness against chronic kidney disease

  • Biomed Pharmacother. 2024 Oct:179:117329. doi: 10.1016/j.biopha.2024.117329.
Qing Zhang 1,  Zhiying Qin 2,  Qiang Wang 3,  Liqian Lu 4,  Jiao Wang 4,  Manman Lu 4,  Pei Wang 5,  Dongwei Liu 1,  Chunyu Zhou 6,  Zhangsuo Liu 7
Affiliations

Affiliations

  • 1 Research Institute of Nephrology, Zhengzhou University, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Traditional Chinese Medicine Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Province Research Center for Kidney Disease, Zhengzhou, China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China.
  • 2 Department of Pharmacy, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China; Henan Engineering Research Center for Application and Translation of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China.
  • 3 Department of Nephrology, The Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China.
  • 4 Research Institute of Nephrology, Zhengzhou University, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Province Research Center for Kidney Disease, Zhengzhou, China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China.
  • 5 Blood Purification Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 6 Research Institute of Nephrology, Zhengzhou University, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Province Research Center for Kidney Disease, Zhengzhou, China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China; Blood Purification Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. Electronic address: fcczhcy@zzu.edu.cn.
  • 7 Research Institute of Nephrology, Zhengzhou University, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Traditional Chinese Medicine Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Province Research Center for Kidney Disease, Zhengzhou, China; Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China. Electronic address: Zhangsuoliu@zzu.edu.cn.
PMID: 39180793 DOI: 10.1016/j.biopha.2024.117329
Abstract

ZCL-278 is a selective small molecule specifically inhibiting the Cdc42-intersectin interaction, yet its in-vivo pharmacokinetic and pharmacodynamic properties against renal diseases had not been determined. Thus, our study explored the absorption, distribution and excretion of ZCL-278 as well as its pharmacological efficacy against chronic kidney disease (CKD). With the optimized detection method, absolute oral bioavailability of ZCL-278 was determined as 10.99 % in male and 17.34 % in female rats. ZCL-278 was rapidly and abundantly distributed in various tissues, especially the kidney and heart, while few excreted through urine and feces. In the adenine-induced CKD mice, the increased plasma creatinine and urea, the decreased body weight as well as the renal pathological alterations, including vacuolization of renal tubular epithelial cells, granular degeneration, cell flattening, luminal dilation, and cylindruria, were significantly ameliorated after ZCL-278 administration. Moreover, ZCL-278 could also reverse the increased intensities of renal inflammation and fibrosis in the CKD mice. These results clarified the pharmacokinetics of ZCL-278 in rats and preliminarily indicated that ZCL-278 has favorable pharmacodynamic properties for CKD primed for lead development and optimization, warranting further drug development.

Keywords

Cdc42; Chronic kidney disease; Pharmacokinetics; Small-molecule inhibitor; ZCL-278.

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